In chronic smokers, abstinence from nicotine produces aversive cognitive symptoms which predict relapse. Understanding the genetic and neural mechanisms that underlie these abstinence-induced cognitive deficits is therefore critical to develop more efficacious treatments for nicotine addiction. The overall goal of this R03 application is to examine whether genetic variation in catechol-O-methyltransferase (COMT val158met polymorphism) is associated with adverse cognitive effects of nicotine abstinence in chronic smokers. COMT is a methylation enzyme that degrades dopamine and regulates dopamine levels in the frontal cortex. The COMT gene has a common functional polymorphism (val158met);the val allele is associated with an increase in COMT enzyme activity and a decrease in brain dopamine levels. Importantly, research by our group and others has linked the COMT val allele with nicotine dependence and smoking relapse. New data from our laboratory suggest that the increased smoking relapse risk in COMT val allele carriers may be attributable to an exacerbation of cognitive deficits during nicotine abstinence in this subgroup of smokers. However, this initial study was small and was limited to assessment of working memory. Given the validated relationship of this polymorphism with smoking relapse, a larger and broader examination of the role of COMT val158met in abstinence-induced cognitive function is clearly needed. Toward this end, we propose to examine the association of COMT val158met with cognition and brain function using a nicotine abstinence challenge laboratory paradigm validated in our prior work. Forty eligible smokers (20 met/met and 20 val/val) will participate in two blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) sessions occurring 1-2 weeks apart in counterbalanced order: smoking as usual vs. overnight (= 14 hours) abstinent. BOLD fMRI will be acquired while they perform validated tasks probing key components of executive cognitive function, including sustained attention (continuous performance task;CPT), working memory (N-back), and behavioral inhibition (Go-No-Go). These tasks have been selected based upon their sensitivity to abstinence effects and/or COMT genotype associations. The primary outcomes are task-related BOLD activation and performance during abstinence vs. satiety. Data generated from this study may further establish cognitive measures as important endophenotypes for genetic studies of nicotine dependence. The novel genetics and neuroimaging approach proposed can also be applied in the future to study the role of genetic variation in other drug addiction phenotypes. PUBLIC HEALTH RELEVANCE: This study will improve our understanding of individual differences in cognitive deficits that arise during abstinence from smoking and predict relapse.